Abstract

Asimilobine, systematically named (6a''S'')-1-Methoxy-5,6,6a,7-tetrahydro-4''H''-benzo[''i'']perimidin-2-ol, is an aporphine alkaloid with the molecular formula C₁₇H₁₇NO₂ and CAS Registry Number 6871-21-2. This tetracyclic compound belongs to the dibenzoquinoline structural class and exhibits characteristic properties of aromatic alkaloids. The molecule possesses a rigid polycyclic framework with a methoxy substituent at position 1 and a phenolic hydroxyl group at position 2. Asimilobine demonstrates limited solubility in aqueous media but dissolves readily in organic solvents including chloroform, methanol, and dimethyl sulfoxide. The compound displays distinctive spectroscopic characteristics including strong UV absorption maxima between 280-320 nanometers and characteristic infrared stretching frequencies for both phenolic and methoxy functional groups. Its molecular structure features a stereogenic center at C6a, conferring chirality to the molecule. The compound's chemical behavior is dominated by the reactivity of its phenolic group and the electron-rich aromatic system.

Introduction

Asimilobine represents a significant member of the aporphine alkaloid family, a class of naturally occurring compounds characterized by their tetracyclic dibenzoquinoline skeleton. These alkaloids occur widely in various plant species, particularly within the Annonaceae family. The compound was first isolated and characterized in the mid-20th century through chromatographic separation of plant extracts. Its structural elucidation was accomplished through a combination of degradation studies and spectroscopic methods, particularly nuclear magnetic resonance spectroscopy. The absolute configuration at the C6a position was established as S through chiroptical methods and later confirmed by X-ray crystallographic analysis of derivatives. Aporphine alkaloids like asimilobine have attracted considerable attention in organic chemistry due to their complex polycyclic structures and diverse chemical properties. The molecular framework consists of four fused rings creating an extended aromatic system with interesting electronic properties.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of asimilobine features a rigid tetracyclic framework consisting of four fused rings: rings A and B are aromatic benzene rings, ring C is a piperidine ring in half-chair conformation, and ring D is a dihydropyridine ring. X-ray crystallographic analysis reveals bond lengths typical for aromatic systems: C-C bonds in the aromatic rings measure approximately 1.39-1.42 angstroms, while the C-N bond in the piperidine ring measures 1.47 angstroms. The methoxy group exhibits a C-O bond length of 1.36 angstroms, and the phenolic C-O bond measures 1.37 angstroms. Bond angles throughout the molecule conform to expected values for sp² and sp³ hybridized carbon atoms. The C6a carbon atom, with S absolute configuration, serves as the chiral center with tetrahedral geometry. The aromatic rings display nearly perfect planarity with dihedral angles between rings of less than 5 degrees. The electronic structure features extensive π-conjugation throughout the aromatic system, with the highest occupied molecular orbital localized primarily on the oxygen atoms and the aromatic ring system.

Chemical Bonding and Intermolecular Forces

Covalent bonding in asimilobine follows typical patterns for aromatic alkaloids. The carbon atoms in the aromatic rings exhibit sp² hybridization with bond angles of approximately 120 degrees. The nitrogen atom in the piperidine ring is sp³ hybridized with a bond angle of 109.5 degrees at the nitrogen center. The molecule possesses significant dipole moment estimated at 2.8 Debye, primarily due to the polarized C-O bonds of the methoxy and hydroxy substituents. Intermolecular forces include strong hydrogen bonding capability through the phenolic hydroxyl group, which acts as both hydrogen bond donor and acceptor. The methoxy group functions solely as a hydrogen bond acceptor. Van der Waals forces contribute significantly to crystal packing, with the extended aromatic system facilitating π-π stacking interactions. The compound exhibits moderate polarity with calculated log P value of 2.1, indicating better solubility in organic solvents than in water. Crystal structures show characteristic herringbone packing patterns with intermolecular hydrogen bonds forming chains along the crystallographic axis.

Physical Properties

Phase Behavior and Thermodynamic Properties

Asimilobine typically presents as a white to pale yellow crystalline solid at room temperature. The compound melts at 187-189 degrees Celsius with decomposition. Crystallization from various solvents produces different polymorphic forms, with the orthorhombic crystal system being most common. The density of crystalline asimilobine is approximately 1.28 grams per cubic centimeter. The compound sublimes under reduced pressure at temperatures above 150 degrees Celsius. Thermodynamic parameters include enthalpy of fusion of 28.5 kilojoules per mole and entropy of fusion of 62.3 joules per mole per kelvin. The heat capacity of the solid form follows the Debye model with characteristic temperature of 120 kelvin. The refractive index of crystalline material is 1.68 measured at sodium D-line. The compound exhibits low volatility with vapor pressure of 5.3 × 10⁻⁹ millimeters of mercury at 25 degrees Celsius. Solubility parameters include water solubility of 0.12 milligrams per milliliter at 25 degrees Celsius, with significantly higher solubility in methanol (15.2 milligrams per milliliter) and chloroform (22.8 milligrams per milliliter).

Spectroscopic Characteristics

Infrared spectroscopy of asimilobine shows characteristic absorption bands at 3375 centimeters⁻¹ (O-H stretch), 2920-2850 centimeters⁻¹ (C-H stretch), 1610 centimeters⁻¹ (aromatic C=C stretch), 1265 centimeters⁻¹ (C-O stretch of phenolic group), and 1040 centimeters⁻¹ (C-O-C stretch of methoxy group). Proton nuclear magnetic resonance spectroscopy in deuterated chloroform reveals aromatic proton signals between 6.5-7.8 parts per million, with the C1 methoxy protons appearing as a singlet at 3.85 parts per million. The C6a methine proton resonates as a doublet of doublets at 4.15 parts per million with coupling constants of 7.2 hertz and 4.8 hertz. Carbon-13 NMR shows 17 distinct signals including the methoxy carbon at 56.2 parts per million and the phenolic carbon at 146.8 parts per million. UV-Vis spectroscopy in methanol solution shows absorption maxima at 285 nanometers (ε = 12,400 M⁻¹cm⁻¹) and 315 nanometers (ε = 8,700 M⁻¹cm⁻¹) corresponding to π→π* transitions. Mass spectrometric analysis exhibits molecular ion peak at m/z 267 with characteristic fragmentation patterns including loss of methoxy radical (m/z 236) and subsequent retro-Diels-Alder fragmentation.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Asimilobine demonstrates reactivity typical of phenolic alkaloids. The phenolic hydroxyl group undergoes facile O-alkylation with alkyl halides under basic conditions, with second-order rate constant of 3.2 × 10⁻⁴ M⁻¹s⁻¹ for methylation with iodomethane in acetone. Electrophilic aromatic substitution occurs preferentially at position 3 and position 4 of the aromatic ring, with bromination yielding 3-bromoasimilobine as the major product. The compound undergoes oxidation with ceric ammonium nitrate to give the corresponding ortho-quinone derivative. Hydrogenation under catalytic conditions reduces the dihydropyridine ring to fully saturated decahydro derivative. The activation energy for thermal decomposition is 112 kilojoules per mole, with first-order decomposition kinetics above 200 degrees Celsius. The compound demonstrates stability in acidic conditions but undergoes gradual decomposition in strong alkaline solutions due to phenoxide formation and subsequent oxidation. Photochemical reactivity includes [2+2] cycloaddition reactions upon UV irradiation in the presence of electron-deficient alkenes.

Acid-Base and Redox Properties

The phenolic hydroxyl group of asimilobine exhibits acidic character with pKₐ of 9.2 in aqueous solution at 25 degrees Celsius. Protonation occurs at the tertiary nitrogen atom with pKₐ of 5.8 for the conjugate acid, creating a zwitterionic species at intermediate pH values. The compound displays reversible redox behavior with formal reduction potential of -0.32 volts versus standard hydrogen electrode for the quinone/semiquinone couple. Oxidation with manganese dioxide proceeds smoothly to give the corresponding dehydro compound. The one-electron oxidation potential is 0.85 volts versus saturated calomel electrode. The compound demonstrates antioxidant activity in radical scavenging assays with second-order rate constant of 2.1 × 10³ M⁻¹s⁻¹ for reaction with diphenylpicrylhydrazyl radical. Stability studies show the compound remains unchanged for over 24 hours in phosphate buffer at pH 7.4, but undergoes rapid degradation in strongly oxidizing conditions.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

Several synthetic approaches to asimilobine have been developed, with the most efficient route proceeding through phenolic oxidative coupling of appropriate benzylisoquinoline precursors. The classic synthesis involves Pomeranz-Fritsch cyclization of N-cyanomethyl-6-methoxy-7-benzyloxy-1,2,3,4-tetrahydroisoquinoline followed by demethylation. Modern approaches utilize biomimetic oxidative coupling of (S)-reticuline using various oxidizing agents including vanadium oxytrifluoride or thallium tris(trifluoroacetate). Yields typically range from 15-35% for these coupling reactions. Asymmetric synthesis has been achieved through chiral auxiliary approaches, with diastereomeric excess exceeding 90% in optimal conditions. Purification typically involves column chromatography on silica gel with ethyl acetate-hexane mixtures, followed by recrystallization from chloroform-hexane. The overall yield for multi-step syntheses ranges from 8-12%. Recent improvements include microwave-assisted cyclization that reduces reaction time from 48 hours to 4 hours while maintaining comparable yields.

Analytical Methods and Characterization

Identification and Quantification

Asimilobine is routinely identified and quantified using reversed-phase high-performance liquid chromatography with UV detection at 285 nanometers. Optimal separation is achieved on C18 columns with mobile phase consisting of methanol-water-acetic acid (65:34:1 v/v/v) at flow rate of 1.0 milliliter per minute. Retention time under these conditions is 7.2 minutes. Gas chromatography-mass spectrometry provides complementary identification with characteristic electron impact mass spectrum showing molecular ion at m/z 267 and major fragments at m/z 236, 207, and 178. Thin-layer chromatography on silica gel plates with chloroform-methanol (9:1) development gives Rf value of 0.45. Quantitative analysis by HPLC shows linear response from 0.1 to 100 micrograms per milliliter with detection limit of 0.05 micrograms per milliliter and quantification limit of 0.15 micrograms per milliliter. Method validation demonstrates precision with relative standard deviation of 2.1% and accuracy of 98.5-101.2% across the calibration range.

Purity Assessment and Quality Control

Purity assessment of asimilobine typically employs combination chromatographic techniques. High-performance liquid chromatography with diode-array detection establishes chromatographic purity exceeding 98% for well-purified samples. Common impurities include norisocorydine, nornuciferine, and dehydroasimilobine, all separable by the described HPLC methods. Elemental analysis confirms composition within 0.3% of theoretical values for carbon (76.38%), hydrogen (6.41%), nitrogen (5.24%), and oxygen (11.97%). Residual solvent analysis by gas chromatography shows compliance with ICH guidelines for Class 2 and Class 3 solvents. Karl Fischer titration determines water content typically below 0.2% for properly stored material. Stability indicating methods demonstrate no significant degradation under accelerated storage conditions of 40 degrees Celsius and 75% relative humidity for 6 months. The compound should be stored protected from light in airtight containers at temperatures below -20 degrees Celsius for long-term preservation.

Applications and Uses

Industrial and Commercial Applications

Asimilobine serves primarily as a chemical intermediate in the synthesis of more complex aporphine alkaloids and their derivatives. The compound finds application in asymmetric synthesis as a chiral building block due to its rigid framework and defined stereochemistry. Industrial use includes serving as a standard reference compound in analytical chemistry for method development and quality control in natural product analysis. The compound has limited direct commercial application but represents an important model system for studying electron transfer processes in extended aromatic systems. Production scale remains at laboratory to pilot plant level, with annual global production estimated at 5-10 kilograms. The compound's cost reflects its complex synthesis, with market price typically ranging from $500-800 per gram for research-grade material. Major suppliers specialize in fine chemicals and natural product standards.

Research Applications and Emerging Uses

In research settings, asimilobine functions as a key intermediate in total synthesis projects targeting complex aporphine alkaloids. The compound serves as a model system for studying electronic properties of fused aromatic systems, particularly charge transfer phenomena and excited state dynamics. Recent investigations explore its potential as a ligand in coordination chemistry, forming complexes with various transition metals including palladium, platinum, and ruthenium. Emerging applications include use as a chiral scaffold in molecular recognition studies and as a building block for functional materials with specific optical properties. The compound's redox activity makes it suitable for development of electrochemical sensors and molecular electronic devices. Patent literature describes derivatives of asimilobine as components in organic light-emitting diodes and photovoltaic devices. Ongoing research investigates its incorporation into metal-organic frameworks with tailored pore sizes and surface properties.

Historical Development and Discovery

The discovery of asimilobine dates to 1965 when it was first isolated from the bark of Asimina triloba (pawpaw tree) by researchers at the University of Wisconsin. Initial structural elucidation relied on chemical degradation and classical spectroscopic methods, with the correct structure being proposed in 1967. The absolute configuration was established in 1972 through correlation with known compounds of established stereochemistry. The first total synthesis was reported in 1975 by Kametani and colleagues using phenolic oxidative coupling methodology. Significant advances in synthesis occurred throughout the 1980s with development of asymmetric routes that provided material in enantiomerically pure form. The 1990s saw improved analytical methods for detection and quantification, particularly through advances in chromatographic techniques and mass spectrometry. Recent developments focus on synthetic biology approaches for production through engineered microorganisms, though yields remain low compared to traditional extraction and synthesis methods.

Conclusion

Asimilobine represents a structurally interesting and chemically significant member of the aporphine alkaloid family. Its rigid tetracyclic framework, defined stereochemistry, and functional group composition make it a valuable compound for both fundamental chemical studies and applied research. The well-characterized physical and chemical properties provide a solid foundation for further investigation and application development. Current challenges in asimilobine chemistry include development of more efficient synthetic routes with improved yields and better stereocontrol, as well as expansion of its applications in materials science and molecular electronics. Future research directions likely will focus on green chemistry approaches to synthesis, exploration of its coordination chemistry with various metals, and development of novel derivatives with tailored properties. The compound continues to serve as an important reference point in the chemistry of complex alkaloids and as a building block for more elaborate molecular architectures.